Esters of amino propanes



Patented May 7, 1929.

UNITED STATES PAT/KENT OFFICEHVT WALTER scnonnnna AND HERBERT scno'r'rn, or BERLIN, GERMANY, ASBIGNOBS 'ro THE FIRM cnnmscnn FABRIK aur ACTIEN vomu. E." scnnnme), or 13mm,

GERMANY.

nsrnas or AMINO raoranns;

No Drawing. Application filed March 18, 1925, Serial No. 16,1?12, and in Germany March 25, 1924.

Our invention refers to new chemical products adapted for pharmaceutical use and to the method of making same. It more particularly relates to the production of esters of amino propanes etherified in ,B-position and which correspond to the formula 15 wherein X is either an alkyl or aryl or a product ofsubstitution thereof, Y an alkyl, R a hydrogen atom or an alkyl or an aryl, R a hydrogen atom or an alkyl, R' a hydrogen "atom or an alkyl or R" and R together in certain cases a cyclic radical, and wherein the two remaining affinities of the nitrogen can be satisfied by the addition of an alkyl halide.

The new esters answering this description form colourless or, almost colourless salts which are soluble in water and alcohol and are adapted, more especially in the form of salts, for therapeutical use. If heated with alkali, the bases lose their acyl radical.

These esters are produce in two separate stages, viz: r

(A Production of the amino propanes etherlfied in B-position 113) Etherification of these products. I order to produce the compounds mentioned under (A), we proceed by treating an unsaturated alcohol, for instance allyl alcohol, cinnamic alcohol or isocrotonyl alcohol, in an alcoholic medium, for instance ethyl alcohol or methyl alcohol, with a salt of hi- 40 valent merc ry,"*w,hereby the mercury salt radical and iitlthe same time an oxalkyl is added on the double bond. The ether derivatives containing mercury'which are thus obtained are then converted into the corresponding halogen compou and the halogen is replaced by amines.'

The amino compounds thus produced are then converted into esters in a well known manner. I A. In order to produce the amino propanes in ,B-position, we prefer proceeding for instance as follows 3 Example 1.

by evaporation and after dilutingwith waterthe residue neutralized with bicarbonate of soda. Upon an aqueous solution of potas- SlllIIl bromide in excess bemg added, an oil separates out which, on being triturated with some ethyl acetate, crystallizes. After drying in the air, the compound is boiled in aqueous suspension or better still in a solution of ethyl acetate with one molecule iodine during about 20 minutes, until decolorization ensues, whereupon the mercury salt is removed and the residue is subjected to distillation.

The a hydroxy ,8 methoxy 'y iodine-propane which under a pressure of 0.4 mm. boils at about (iii-66 0., is heated with an equal quantity by weight of diethyl amine during two hours to 100. The liquid which on cooling partly solidifies is taken up with an equal quantity of water. On the addition of po tassium carbonate the a-hydroxy-B-methoxy- -diethylamino propane is separated out in the form of an oil which boils under a pressure of 1.2 mm. at about 62-63", has the strong smell and reaction of a base and readily dissolves in ether.

Example 2.

which, on the solution being evaporated, remains as a crystalline mass. After recrystallization from alcohol, it forms pointed shining needles arranged in star-fashion, melting about at 108-109 C. (not corrected) and being readily soluble in water.

Example 3.

By proceeding as described with reference to Example 1, using, however, methyl alcohol instead of ethyl alcohol as a solvent, the corresponding ethoxy compounds are obtained.

The u-hydroxy-B-ethoxy-y mercur1e bromide is a crystalline powder dissolving in water only with difficulty and which can be recrystallized from ethyl acetate. On being treated with iodine in the manner described with reference to Example 1, there results 01-- If 3 grams of the iodine hydrine described with reference to Example 1 are heated during 2 to 3 hours at 100 with a solution of ammonia in methyl alcohol saturated at 0 0., there results the a-hydroxy-B-methoxyy-amino propane which forms a thick oil boiling under 10 mm. pressure at 104105 0.

Example 5.

5 grams of the iodine hydrines mentioned with reference to Examples 1 and 3 are heated during 5 hours with 7 grams of an aqueous 33 per cent solution of methyl amine. The compounds obtained GHzOH-OHOCHr-CH1NH and CHIOHCHOCZHICHINH are oils readily soluble in water, ether and alcohol. The compound mentioned in the first place boils under 12 mm. pressure at about 75, the other compound under 13 mm. pressure at about 8991. The picric acid salt of this latter compound, if recrystallized from alcohol, melts at about 92-93 C.

Example 6.-

10 grams of the iodine hydrine described with reference to Example 1 are heated during 45 minutes in a Water-bath with 10 grams piperidine. After treating the mixture as usual, there is obtained the compound which forms a colourless oil boiling under 0.3 mm. pressure at about 8182. It is readily soluble in water, ether and alcohol and shows a vigorous basic reaction.

Example '2.

To a solution of 4 grams cinnamic alcohol in 30 ccms. methyl alcohol is added a solution of 9 grams mercuric acetate in ccms. methyl alcohol. After the lapse of 10 minutes,-no mercury can be found with the aid of ammonium sulfide. The solution is now evaporated in vacuo, the residual syrup is taken up with water andneutralized with bicarbonate of soda, and an equeous solution of'4.6 grams potassium bromide is added. An oil separates out which solidifies on being triturated and which, on being recrystallized from chloroform, has a melting point of about 110-111 C. The compound thus" obtained is the u-hydroxy-B-methoxy- -mercuric bromide-y-phenyl propane.

In the same manner the whydroxy-B- ethoxy- -mercuric chloride- -phenyl propane can be obtained, if ethyl alcohol is used as a solvent and sodium chloride as a precipitant. This compound melts at about 86, dissolves with difliculty in petroleum ether and is easily soluble in methyl and ethyl alcohol, ethyl acetate and hot benzene.

If the mercury bromide compound is heated with. one molecule iodine in an ethyl acetate solution, the iodine is decolourized after two minutes. After removing the mercury salt and removing the solvent by distillation, there remains the a-hyd'roxy-B-methoxyiodine- -phenyl propane forming a colourless syrup which does not distil over even in a high vacuum, but deflagrates at about 120 under separation of iodine. This compound is insoluble in water and dissolves readily in ethyl acetate, chloroform and ether.

If heated with 3 molecules diethyl amine to 100, there takes place within one hour the exchange of the halogen for the amine.

-After treating as usual, there is produced a slightly coloured oil dissolving in water only with difliculty and boiling partly at 12S-125 in a high vacuum.

B. The etherification of the amino propanes etherified in B-position is obtained for instance as follows Example 8.

whydroxy-B-methoXy- -diethylamino propane is dissolved in an equal quantity by weight of benzene and a solution of 1.5 molecules p-nitro benzoyl chloride in the fivefold quantity of benzene is added. The oil which precipitates at once, solidifies after a short time, forming a crystalline mass which is the hydrochloride of the mtro benzoate no.- 01111-00-0-0111-011-com-om-mouzd- If this compound is recrystallized from a large quantity of benzene or amyl alcohol, ther esults the hydrochloride of a-(p-nitro ben zpy )-,B-methoxy- -di'ethyl amino propane forming fine lon pointed needles melting at about 143-1i4r The nitro compound can be converted into the amino compound by dissolving it in concentrated hydrochloric acid and reducing with the calculated quantity'of stannous chloride, care being taken to prevent the temperature from rising above After neutraliz ingthe hydrochloric acid with caustic alkali.

and rendering alkaline with potassium carbonate there is obtained by extraction with ether the a-(p-amino benzoyl) -,B.-methoxydiethyl amino propane.

H O CH;

CaHb

forming avthick colourless oil insoluble in water and soluble in organic solvents. The

hydrochloride forms minute needles having the melting point 159 (not corrected) it is readily soluble in Water withneutral reaction and acts as a vigorous anesthetic.

Example 9.

By starting from u-hydroxy-B-ethoxydiethylamino propane and proceeding as described with reference to Example 8, there is obtained a-(p-nitro benzoyl) -,8-ethoxy-y-diethyl amino propane and by reduction the corresponding amino compound H 0- CIHI /C3Hl II: N

The hydrochloride of the nitro benzoyl compound is a crystal powder consisting of slightly yellow needles readily soluble in water and melting at about 152. The hydrochloride of the amino benzo 1 compound which also melts at about 152 1s a colourless .crystal powder readily soluble in water and alcohol. It acts as ananesthetic in a similar manner as the correspondingly methoxy compound.

- Example 10.

The a-hydroxy-B-methoxy- -piperidinopro ane if treated in the manner above descri ed is converted into a-(p-nitro benzoyl) fl-methoxy- -piperidino propane, the hydrochloride of which crystallizes from ethyl acetate in largefointed crystals melting at about 163164 an alcohol, while onl acetate.

The hydrochloride of a-amino benzoyl-,8- methoxy- -piperidino propane with difiiculty in ethyl a-hydroxy fl-methoxy- -trimethy1ammonium iodide propaneiis converted into its acetyl derivative by short boiling with acetyl y chloride in excess or stilhmore convenient by dissolving in pyridine and adding 1.2 molecules acetic acid. anhydride. The a-aceto-,B-methoxy- -trimethy1 ammonium iodide propane o ,oH,.o

.H -0-OH| HKl-NKJHIMI crystallizes at once in pure form from the mixture of pyridine and acetic acid anhydride and forms large colourless crystals which melt at about 161-162 and are readily soluble in water, alcohol and dilute acids.

E wample 12.

If molecular quantities of a-hydroxy-B- methoxy- -trimethyl ammonium iodide propane and meta phosphoric acid ethyl ester are allowed to stand at ordinary temperature during some days, the ethyl phosphoric acid ester O-OH1' nd-o om End-mono! is formed. It is a thick slightly brownish syrup readily soluble .in water from which results after neutralization with barium hydroxide an amorphous mono-barium salt which dissolves in water only with a certain diflicultv. v

. Example 13;

By treating the a-hydroxy-B-methoxytrimethyl ammonium iodide propane under readil dissolving in water and vigorous cooling with chlorine sulfonic acid in excess there is obtained under generation of hydrochloric acid the acid sulfate ester of this compound 0: o-orn H com H2 -N(CE|)|I in the form of a thick syrup which is capable of forming salts and readily soluble in water.

The esters of a-hydroxy-,8-1nethoxy- -trimethyl ammonium iodide propane above mentioned have the property of causing peristaltic movements of the intestines.

sponds to the formula wherein X is either an alkyl or aryl or a product of substitution thereof, Y an alkyl, R a hydrogen atom or alkyl or aryl, R a hydrogen atom or alkyl, R a hydrogen atom or alkyl and wherein R" and R' together can also be a cyclic radical, said product, on being heated with an alkali, splitting off its acyl radical and forming with acids and halogen alkyls colorless salts which are soluble in water and alcohol and have valuable therapeutical properties.

2. As a new product an a-amino benzoylfi-alkoxy- -dietl1ylamino propane corresponding to the formula this product being a colourless compound insoluble in water, soluble in organic solvents, splitting oil its acyl radical on being heated with an alkali, and forming with acids and halogen alkyls colourless salts which are soluble in water and alcohol and have valuable therapeutical properties.

ln testimony whereof we afiix our signatures.

WALTER SCHOELLER. HERBERT SCHOTTE. 

